Heart disease is a leading cause of death worldwide. Increasing evidence indicates that apoptosis, associated with detrimental structural and functional alterations, is a major contributor in the progression of cardiac remodeling and heart failure. Thus, preventing the loss of cardiomyocytes becomes critical for the maintenance of normal cardiac function. However, inhibition of cardiac cell death would hold little clinical promise, if it simply resulted in increased survival of dysfunctional cardiomyocytes. Our recent studies suggest that the small heat-shock protein Hsp20 may improve cardiac function and provide protection against cardiomyocyte death. Hsp20 is different from the other members of sHsps in the following respects: 1) It regulates both vasorelaxation and cardiac contractility;2) Overexpression of Hsp20 provides cardioprotection against p-agonist-induced apoptosis and ischemia/reperfusion-induced injury;and 3) Hsp20 contains a unique PKA/PKG phosphorylation site, RRAS, and phosphorylation of this site, significantly increases contractility and cardioprotection in cardiomyocytes. In this project, we propose further studies to elucidate the in vivo role of Hsp20 and its phosphorylation in cardiac contractility, using genetically altered mouse models. Furthermore, since alterations in the levels of Hsp20 and its phosphorylation regulate the heart's responses to stress, we propose to further investigate the efficacy of Hsp20 and specifically phosphorylated Hsp20 in the heart's remodeling process in response to pressure-overload and myocardial infarction. We also propose to determine the therapeutic significance of Hsp20 in the setting of pre-existing heart failure, using in vivo cardiac gene delivery. These studies will provide important information on the functional role of cardiac Hsp20 in vivo under physiological and pathophysiological conditions. Overall, our proposed studies will: a) advance our knowledge on the mechanisms underlying regulation of cardiac contractility and apoptotic cell death by Hsp20;and b) provide valuable insights into the potential benefits of Hsp20 in heart disease.